A Type I/II Photosensitizer with Lysosome-Targeting Capabilities Induces Immunogenic Cell Death in Cancer Cells to Enhance Tumor Immunotherapy

The immunosuppressive microenvironment initially hinders tumors' response to immunotherapy. Enhancing immunotherapy outcomes can be achieved through a strategy that efficiently activates dendritic cells (DCs), T cells, and macrophages within the tumor microenvironment (TME). This study develops a photosensitizer named CPBPDPN-TPA, which is based on dibenzo[<i>a</i>,<i>c</i>]phenazine (DP) and shows an aggregation-induced emission (AIE) and delayed fluorescence. It effectively produces both type I and type II reactive oxygen species (ROS), making it a promising option for photodynamic therapy (PDT). CPBPDPN-TPA selectively accumulates in lysosomes and induces significant lysosomal damage in tumor cells when exposed to white light irradiation. This damage leads to both apoptosis and immunogenic cell death (ICD) via ROS, ultimately preventing tumor progression. Importantly, CPBPDPN-TPA also allows the reprogramming of the TME, inducing CD8+ T-cell infiltration, macrophage M1 polarization, and dendritic cell maturation via activating the STING signaling pathway. The combination of PDT and anti-PD-1 treatment creates a synergistic effect that significantly inhibits tumor growth in vivo. In conclusion, this study proposes a model that improves immunotherapy by combining PDT and PD-1 blockade, greatly enhancing antitumor immunity and inhibiting tumor growth effectively.